There is substantial evidence that in mammals aging, genomic stability, and development and function in the immune system are intricately linked. A striking recent example is the inactivation of the type IA DNA topoisomerase Top3beta, which results in shortened lifespan, aneuploidy in somatic and germ cells, ionizing and UV-B radiation sensitivity, and age-related splenomegaly and autoantibody production. DNA topoisomerases carry out the sequential breakage and rejoining of DNA strands to resolve structures inherent in the requirement for DNA strands to separate during recombination, transcription and replication. Studies in yeast indicate that Top3, a homologue of the mammalian isozymes Top3alpha and Top3beta, is crucial for genome stability and functionally interacts with Sgs1, a member of the RecQ helicase family. Notably, mutations in RecQ helicases have been linked to human genetic disorders characterized by premature aging and/or genomic instability, including Werner and Bloom syndromes. We will employ mouse models carrying inactivated Top3alpha or Top3beta alleles to test the hypothesis that genomic instability from type IA topoisomerase deficiency contributes to the development of phenotypes associated with aging. We will determine the function of Top3beta in the maintenance of genomic stability and response to DNA damage. In this regard, Top3beta-deficient mice develop age-associated alterations in lymphocyte development at younger ages than wild-type controls;we will assess the potential impact of genomic instability induced by Top3beta deficiency on expansion of lymphocyte precursors vs. V(D)J recombination, and will determine whether impaired development of Top3beta-deficient B and T cells results from cell autonomous or non-autonomous mechanisms. Finally, since germline inactivation of Top3alpha resulted in embryonic lethality, we will carry out lymphocyte-specific and inducible inactivation of Top3alpha, thereby facilitating a definitive assessment of type IA topoisomerase function.